Delivery of drugs by the buccal route of administration and therapeutic compositions and methods therefor have been described previously in U.S. Pat. Nos. 3,133,862 to Wershaw et al., 3,536,809 to Applezweig, 3,598,122 to Zaffaroni, 3,598,123 to Zaffaroni, 3,972,995 to Tsuk et al., 4,226,848 to Nagai et al., 4,250,163 to Nagai et al., 4,292,299 to Hicks et al. and 4,615,697 to Robinson. Robinson provides a review of delivery of drugs via mucosal routes and percutaneous routes. Buccal drug delivery systems with bioadhesive polymers as a platform for holding the system in place in the oral cavity after application have been described in the aforementioned U.S. Patents to Tsuk et al., to Nagai et al., to Hicks et al. and to Robinson. In most of these patents the drug is incorporated in a reservoir in the adhesive layer or embedded in the controlled release matrix without the use of any specific agent to promote drug dissolution and thereby enhance the thermodynamic activity of the drug in the matrix.
In U.S. Pat. No. 3,598,123 to Zaffaroni, a microcapsule encloses the drug as an added reservoir embedded in the adhesive layer of the bi-laminate drug delivery system.
Previously, a method of adhering a delivery system was by hydration of a bioadhesive polymer matrix. Adhesion results from the entanglement of the hydrated polymer chains on the surface of the matrix with the glycoproteins of the mucosa. Under mild pressure such entanglement leads to a reinforcement of adhesion due to London dispersion forces (e.g. van der Waal's forces), as well as hydrophobic, ionic and hydrogen bonding forces that contribute to the adhesion strength.
The inclusion of drugs as a dispersion in polyethylene glycols improves both the solubility and disolution rate and thereby improves the bioavailability of poorly water soluble drugs. Their uses in improving solubility and lowering the polarity of a solvent and dielectric constant of aqueous media are documented in Chiou et al., J. Pharm. Sci. 58, 1505 (1969), Ingham, Arch. Biochem. Biophys. 184, 59 (1977), Herrmann et al., Biochim. Biophys. Acta 733, 87 (1983), Arnold et al., Biochim. Biophys. Acta 815, 515 (1985). More specifically, it has been demonstrated previously that partitioning of hydrophobic as well as polar molecules between the membrane and external phase is changed by polyethylene glycols without interacting in a direct manner with macromolecules or other membrane components.
The carboxy-functional polymers disclosed in Robinson are hydratable polymers which are useful for buccal delivery of drugs. These polymers rely solely on the adhesion of the delivery system followed by drug dissolution in the hydrophilic polymer matrix due to a body fluid such as saliva or its aqueous component to effect release of the drug. In these systems, the chemical potential or the thermodynamic activity of the drug is built up to the point of saturation solubility of the drug in the micro-fluid environment of the polymer matrix. Consequently, the drug is released out of the matrix into the buccal interfacial environment at a rate dependent on the saturation solubility of the drug in the body fluid which permeates the matrix. Thus there is little control over the rate of release. Furthermore, for polar drugs, including zwitter-ionic therapeutic compounds such as bio-synthetic peptides which are subject to poor oral bioavailability, there is a lack of a relatively non-polar microfluid environment at the diffusional interface of the polymer matrix and the buccal mucosa. Thus, solubility of these drugs is poor.
The systems presently utilized therefore, are based solely on Fickian diffusion of the drugs through the polymer matrix. Diffusion rates are limited by the low chemical or thermodynamic activity and a highly polar aqueous environment. These limiting factors are detrimental to improved drug partitioning and permeability across the buccal mucosa.
It is recognized that many drugs are relatively insoluble and more lipophilic in their physical-chemical characteristics. Illustrative drugs in different therapeutic classes include estrogens, contraceptives, steroids, androgens, nifedipine, flufenamic acid and its analogs, spironolactone and griseofulvin. Hence improvement in thermodynamic activity of such drugs in a controlled release matrix combined with a favorable drug partitioning environment would facilitate mucosal drug delivery.
The present invention discloses methods and compositions that are capable of providing improved availability for a wide variety of therapeutic agents from a controlled release mucoadhesive carrier system thereby overcoming the shortcomings of the prior art and satisfying the present needs of society.